1. Field of the Invention
This invention relates to new kanamycin C derivatives active against a wide variety of kanamycin-resistant bacteria, and a process for the preparation of these new kanamycin C derivatives. More particularly, this invention relates to new and useful 1-N-(L-4-amino-2-hydroxybutyryl) derivatives of kanamycin C, 3'-deoxykanamycin C and 3',4'-dideoxykanamcyin C, and the preparation thereof.
2. Description of the Prior Art
Butirosin B, that is, 1-N-(L-4-amino-2-hydroxybutyryl)-ribostamycin may be produced by a fermentative method ("Tetrahedron Letters" 28, 2617-2620 (1971)), and 1-N-(L-4-amino-2-hydroxybutyryl) derivatives of kanamycin A and kanamycin B are synthesized (U.S. Pat. No. 3,781,268 (1973)). 1-N-(L-4-amino-2-hydroxybutyryl) derivatives of other some aminoglycosidic antibiotics are also synthesized (U.K. Pat. No. 1,426,908 (published in Mar. 1976)). Furthermore, deoxy derivatives of kanamycins are also synthesized on the basis of the previous findings which were obtained by H. Umezawa et al. with respect to the mechanism of resistance of bacteria to aminoglycosidic antibiotics owing to various inactivating enzymes produced by the resistant bacteria. For instance, 3',4'-dideoxykanamycin B and 3'-deoxykanamycin B are synthesized which are active against the resistant bacteria producing aminoglycoside 3'-phosphotransferase (U.S. Pat. Nos. 3,753,973 and 3,929,762; and H. Umezawa's "Advances in Carbohydrate Chemistry and Biochemistry" 30, 183 (1974) and "Drug Action and Drug Resistance in Bacteria" 2, 211 (1975)). 3',4'-Dideoxykanamycin B has been used widely in therapeutic treatment of infections caused by a variety of the resistant bacteria, including Pseudomonas aeruginosa. However, it has been found that these deoxy derivatives of kanamycin B do not inhibit the growth of such resistant bacteria which are capable of producing the aminoglycoside 6'-acetyltransferase and 2"-nucleotidyltransferase. As a result of a further research, we have succeeded in synthetically converting the 6'-amino group of kanamycin B or its deoxy derivatives into hydroxyl group and thereby producing kanamycin C and its deoxy derivatives which inherently cannot be inactivated by the 6'-acetyltransferase (see co-pending U.K. Patent Application No. 12266/77 and co-pending U.S. Pat. Application Ser. No. 799,806). However, kanamycin C, 3'-deoxykanamycin C and 3',4 '-dideoxykanamycin C so obtained are not able to inhibit the growth of such resistant bacteria producing the 2"-nucleotidyltransferase.